When lithium carbonate is administered to manic-depressive subjects over a period of time, the rate constant for efflux of lithium from erythrocytes into an in vitro medium is gradually repressed, sometimes to less than 50 percent of its initial value for the individual subject. Prior studies on the mechanism of lithium efflux had shown that efflux could be inhibited by N-ethyl maleimide, ruthenium red, and phloretin, all of which have been demonstrated to inhibit the calcium ATPase of erythrocyte membranes. In contrast, the disulfite ion, which we had shown to be capable of activating lithium efflux, and which we have recently found to promote the activation of calcium ATPase by its own activator, calmodulin, can itself be antagonized, with respect to activation of lithium efflux, by trifluoperazine. Since the latter substance is regarded as a specific inhibitor of calmodulin-activated calcium ATPase, it appears that the portion of lithium efflux which is augmented by disulfite depends, in fact, on the calmodulin-calcium ATPase system. This particular portion of lithium efflux is also the component that is inhibited by chronic lithium ingestion. The current year's work on this project will therefore concentrate on determining in more detail what happens to the calmodulin-CaATPase system as a result of chronic ingestion of lithium carbonate.